The research that is outlined in this proposal is aimed at creating a fundamentally new class of surfactants termed, umbrella - like amphiphiles (ULA's). The ultimate goal of this program is to develop these ULA's into novel carriers that can be used to promote the transport of polar, hydrophilic drugs across the plasma membrane of cells, thereby enhancing drug efficacy. Because antisense oligonucleotides (oligos) now show considerable promise for the treatment of life-threatening diseases such as cancer and AIDS, and because cellular entry has been identified as a- major hurdle which limits their therapeutic potential, this three-year program focuses sharply on the use of oligos as paradigms. It is emphasized that the ULA concept addresses the general problem of transporting hydrophilic drugs across the plasma membrane and that other viable ULA-drug conjugates should, in principal, be possible; e.g., hydrophilic peptides that function as DNA - regulating factors. The specific aims of this research are: (i) to synthesize a homologous series of facial amphiphiles of varying flexibility and hydrophilicity, (ii) to covalently attach these amphilphiles to suitable bifunctional, trifunctional, and tetrafunctional molecular scaffolds derived from spermidine (iii) to characterize the conformational behavior of certain ULA- fluorescent probe conjugates in bulk solution and within lipid bilayers, and (iv) to synthesize prototype ULA- antisense oligonucleotide conjugates and to define their ability to diffuse, passively, across liposomal membranes.